Rheumatoid arthritis (RA), a disease of unknown etiology, is characterized by auto-immunity and autoantibodies, synovial inflammation and hyperplasia, cartilage and bone destruction, as well as systemic disorders, in particular impact on the cardiovascular system (McInness & Schett, NEJM 2011; Pieringer H et al., 2011). Multiple pathogenic mechanisms involving both innate and adaptive immunity are at play and contribute differentially in various phases of the disease, and conceivably in different patient subsets. However, no biomarker predicting progression is available yet.
Cytokines play a critical role in progression and control of the disease, as has been exemplified by successful therapy inhibiting key cytokines involved in the disease, such as TNFa and IL-6 or its receptor (Woodrick R et al., 2010). Their effects are pleiotropic and impact nearly all cell types involved in disease.
Tumour Necrosis Factor (TNF, also known as TNFa or TNFa) is a pro-inflammatory cytokine. TNFa plays a role in the induction of other inflammatory cytokines. Anti-TNFa therapy has a remarkable track record at improving RA and the safety of the therapy is well characterized (Canete & Pablos, 2013).
However, anti-cytokine therapies have limitations, for example upon anti-TNFa treatment approximately 40% of patients never respond, and only 20% of patients experience a major reduction in disease activity. Furthermore, many patients do not achieve remission and most lose their response to anti-TNFa therapies within two to three years. IL-6R inhibition bears the promise to show incremental activity and provide additional benefit (Ash et al., 2012).
In view of the above, there is a large unmet clinical need for treatments regarding a more effective suppression of inflammation and halting, or even reversing, disease progression and joint destruction. The ultimate goal is sustained remission for a greater number of patients in RA.
Given the heterogeneity and dynamic nature of the human autoimmune diseases, including redundancy of molecular pathways, it is likely that one will need to perturb multiple redundant and distinct mechanisms to achieve greater and/or broader therapeutic efficacy. Current therapies inhibiting cytokines (Atzeni & Sarzi-Puttini, 2009) or T cell activation are already by themselves immunosuppressive, and combination of the same may lead to unacceptable increase of infection related side effects. This has been shown for e.g. a combination of CTLA-4-Ig and anti-TNFa (Weinblatt, 2007), or anti-TNFa and IL-1RA (Genovese et al., 2004). It is therefore important to identify treatment combinations susceptible to have a major effect on disease, without significantly increasing the risk of side effects.
Interleukin-17 (IL-17, also known as IL-17A) is, like TNFa, a pro-inflammatory cytokine. IL-17 plays a role in the induction of other inflammatory cytokines and chemokines. IL-17 has emerged as a cytokine involved in multiple auto-immune diseases, thought to amplify inflammation and to contribute to chronic tissue destruction and remodelling. IL-17 is produced not only by the Th17 T-helper cell subset, but also among others such as mast cells, which may play a crucial role in RA (Hueber A J, J Immunol 2010). In contrast, the IL-17A receptor (IL-17R) is ubiquitously expressed and signalling via IL-17R drives cytokine, chemokine and prostaglandin secretion from fibroblasts, endothelial and epithelial cells as well as increasing expression of cell adhesion molecules. IL-17 also induces TNFa and IL-1 secretion from macrophages, amplifying inflammation and tissue destruction. Finally, by inducing RANKL, IL-17 is thought to have a major impact on osteoclastogenesis and hence bone destruction (Kehlen et al., 2002; Li et al., 2010; Sadik et al, 2011; van den Berg & Miossec, 2009).
IL-17 neutralizing antibodies reduce severity and incidence of mouse RA model of collagen induced arthritis, and high levels of IL-17A can be detected in the synovial fluid of inflamed joints from RA patients (Ziolkowska et al.; Kotake et al.; Hellings et al.). Current clinical experience with anti-IL-17 antibodies suggests that the level of immunosuppression may be manageable, which make it attractive for combinations with other therapies (Koenders et al).